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The no‐reflow phenomenon is a potential contributor to poor outcome despite successful thrombectomy. There are multiple proposed imaging‐based definitions of no‐reflow leading to wide variations in reported prevalence. We investigated the agreement between existing imaging definitions and compared the characteristics and outcomes of patients identified as having no‐reflow. Methods: We performed an external validation of 4 existing published definitions of no‐reflow in thrombectomy patients with extended Thrombolysis in Cerebral Infarction scale 2c to 3 (eTICI2c‐3) angiographic reperfusion who underwent 24‐hour perfusion imaging from 2 international randomized controlled trials (EXTEND‐IA TNK part‐1 and 2) and a multicenter prospective observational study. Receiver‐operating‐characteristic and Bayesian‐information‐criterion (BIC) analyses were performed with the outcome variable being dependent‐or‐dead at 90‐days (modified Rankin Score [mRS] ≥3). Results: Of 131 patients analyzed, the prevalence of no‐reflow significantly varied between definitions (0.8–22.1%; p < 0.001). There was poor agreement between definitions (kappa 5/6 comparisons <0.212). Among patients with no‐reflow according to at least 1 definition, there were significant differences between definitions in the intralesional interside differences in cerebral blood flow (CBF) (p = 0.006), cerebral blood volume (CBV) (p < 0.001), and mean‐transit‐time (MTT) (p = 0.005). No‐reflow defined by 3 definitions was associated with mRS ≥3 at 90 days. The definition of >15% CBV or CBF asymmetry was the only definition that improved model fit on BIC analysis (ΔBIC = −8.105) and demonstrated an association between no‐reflow and clinical outcome among patients with eTICI3 reperfusion. Conclusions: Existing imaging definitions of no‐reflow varied significantly in prevalence and post‐treatment perfusion imaging profile, potentially explaining the variable prevalence of no‐reflow reported in literature. The definition of >15% CBV or CBF asymmetry best discriminated for functional outcome at 90 days, including patients with eTICI3 reperfusion. ANN NEUROL 2024;96:1104–1114 [ABSTRACT FROM AUTHOR]

Objectives: To review evidence regarding the impact of physical activity interventions for preventing and managing type 2 diabetes in Aboriginal and Torres Strait Islander Australians. Study design: We searched for published reports of physical activity interventions for preventing and managing type 2 diabetes in Indigenous adults (18 years or older). There were no exclusion criteria regarding study type or duration, frequency, length, or intensity of physical activity, except that short term interventions were excluded. We assessed the quality of each study using the Joanna Briggs Institute (JBI) critical appraisal tools and the ethical and methodological quality of studies from an Indigenous Australian perspective with the Centre of Research Excellence in Aboriginal Chronic Disease Knowledge Translation and Exchange (CREATE) Critical Appraisal Tool. Data sources: MEDLINE; Scopus, Embase (Elsevier); Cumulative Index to Nursing and Allied Health Literature (CINAHL), Sports Discus, PsycINFO (EBSCO); Informit Complete; ProQuest Dissertations and Theses, and ProQuest Health and Medicine; each from their inception to 30 October 2022. Results: The database searches identified 703 potentially relevant records; after removing duplicates and initial screening, the full text of 27 articles was assessed for eligibility. Nine studies met our inclusion criteria: two randomised controlled trials, five cohort studies, one quasi‐experimental study, and one repeated cross‐sectional study. Eight studies were rated as being of low or medium quality (median JBI score, 54%; interquartile range [IQR], 36–64%); seven studies were rated as being of low to medium ethical and methodological quality from the Indigenous perspective (median CREATE score, 50%; IQR, 36–64%). Six studies reported changes in glycated haemoglobin (HbA1c) levels, of which two (both cohort studies) reported significantly lower mean HbA1c levels after the intervention, but only one publication provided detailed results. No randomised controlled trials that investigated the effect of a combination of physical activity and dietary change for Indigenous Australians diagnosed with type 2 diabetes were identified. Differences in study design, outcome variables, and the small number of studies precluded meta‐analysis. Conclusions: Quality research into the impact of physical activity interventions on type 2 diabetes in Indigenous people is sparse. To improve research translation, studies that involve Indigenous community members at all levels of the research process are needed. Registration: PROSPERO CRD42021247496 (prospective). [ABSTRACT FROM AUTHOR]

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4–6] vs MM 5 [4–6], adjusted generalized odds ratio 0.89 [0.53–1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3–6] vs MM 5 [4–6], adjusted generalized odds ratio 1.87 [1.45–2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024;96:887–894 [ABSTRACT FROM AUTHOR]

Objectives Methods Results Interpretation Whereas highly cost‐effective and cost‐saving for patients with small infarcts, whether endovascular thrombectomy (EVT) remains cost‐effective in patients with extensive ischemic injury is uncertain.We conducted a model‐based cost‐effectiveness analysis from the United States, Australian, and Spanish societal perspectives, using a 7‐state Markov model, with each state defined by the modified Rankin Scale (mRS) score. Initial probabilities at 3 months were derived from the SELECT2 trial. All other model inputs, including transition probabilities, health care and non‐health care costs, and utility weights, were sourced from published literature and government websites. Our analysis included extensive sensitivity and subgroup analyses.EVT in patients with large ischemic stroke improved health outcomes and was associated with lower costs from a societal viewpoint. EVT was cost‐effective with a mean between‐group difference of 1.24 quality‐adjusted life years (QALYs), and a cost‐saving of $23,409 in the United States, $10,691 in Australia, and $30,036 in Spain, in addition to uncosted benefits in productivity for patients and carers. Subgroup analyses were directionally consistent with the overall population, notably with preserved cost‐effectiveness in older patients (≥ 70 years) and those with more severe strokes (National Institutes of Health Stroke Scale [NIHSS] ≥ 20). Sensitivity analyses were largely consistent with the base‐case results.EVT demonstrated cost‐effectiveness in patients with large core across different settings in the United States, Australia, and Spain, including older patients and those with more severe strokes. These results further support adaptation of systems of care to accommodate the expansion of thrombectomy eligibility to patients with large cores and maximize EVT benefits. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Summary: Infection and lymphopenia are established bendamustine‐related complications. The relationship between lymphopenia severity and infection risk, and the role of antimicrobial prophylaxis, is not well described. This multicentre retrospective study analysed infection characteristics and antimicrobial prophylaxis in 302 bendamustine‐treated indolent non‐Hodgkin lymphoma patients. Lymphopenia (<1 × 109/L) was near universal and time to lymphocyte recovery correlated with cumulative bendamustine dose. No association between lymphopenia severity and duration with infection was observed. Infections occurred in 44% of patients (50% bacterial) with 27% hospitalised; 32% of infections occurred ≥3 months post bendamustine completion. Infection was associated with obinutuzumab and/or maintenance anti‐CD20 therapy, prior therapy and advanced stage. Twenty‐four opportunistic infections occurred in 21 patients: ten varicella zoster virus (VZV), seven herpes simplex virus (HSV), one cytomegalovirus, one progressive multifocal leucoencephalopathy, one nocardiosis, one Pneumocystis jiroveci pneumonia (PJP) and three other fungal infections. VZV/HSV and PJP prophylaxis were prescribed to 42% and 54% respectively. Fewer VZV/HSV infections occurred in patients receiving prophylaxis (HR 0.14, p = 0.061) while PJP prophylaxis was associated with reduced risk of bacterial infection (HR 0.48, p = 0.004). Our study demonstrates a significant infection risk regardless of lymphopenia severity and supports prophylaxis to mitigate the risk of early and delayed infections. [ABSTRACT FROM AUTHOR]

Interventional clinical trials in epilepsy are typically designed and powered to detect a change in seizure frequency as the primary endpoint, with little consideration given to other benefits or harms of the therapy, or impacts on common epilepsy comorbidities. Desirability of outcome ranking (DOOR) is a novel methodology for evaluating benefits and harms associated with introduction of a new treatment. Multiple outcomes are combined and the resulting combinations are ranked according to their desirability. Herein we describe the adaptation of DOOR for use in therapy trials in epilepsy. Consumers with epilepsy were presented with a selection of measures typically included in epilepsy trials and asked to rank their importance in terms of a desirable outcome and to identify interactions between different seizure control levels and other measures. Seizure control, adverse events, and psychiatric comorbidities were identified as most important, and combinations of these outcomes were ranked to form epilepsy‐DOOR. A separate consumer discussion group verified the appropriateness and accuracy of the ranking. The resultant epilepsy‐DOOR includes 60 possible outcomes, representing high granularity for the assessment of future interventions. It demonstrates the importance of consumer involvement in trial design and presents an alternative to seizure frequency for evaluating new treatments for epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. Methods: In a pooled, patient‐level analysis of the EXTEND‐IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. Results: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8–48.4), and median midline shift was 0mm (IQR = 0–2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89–4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (β = −1.19, 95% confidence interval [CI] = −1.51 to −0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23–0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86–3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95–2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. Interpretation: In this mediation analysis from a pooled, patient‐level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793–804 [ABSTRACT FROM AUTHOR]

Objective: Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates. Methods: Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND‐IA and EXTEND‐IA TNK trials. The primary outcome, thrombolytic‐induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90‐day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression. Results: Among 893 patients included in the primary analysis, thrombolytic‐induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09–2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93–2.14) and second segment (aIRR = 2.07, 95% CI = 0.98–4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04–1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00–1.13). No significant treatment‐by‐time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90‐day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54–3.01) compared to patients who achieved reperfusion following endovascular therapy. Interpretation: Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2023;93:489–499 [ABSTRACT FROM AUTHOR]

Continuous glucose monitoring (CGM) is rapidly becoming a vital tool in the management of type 1 diabetes. Its use has been shown to improve glycaemic management and reduce the risk of hypoglycaemic events. The cost of CGM remains a barrier to its widespread application. We aimed to identify and synthesize evidence about the cost‐effectiveness of utilizing CGM in patients with type 1 diabetes. Studies were identified from MEDLINE, Embase and Cochrane Library from January 2010 to February 2022. Those that assessed the cost‐effectiveness of CGM compared to self‐monitored blood glucose (SMBG) in patients with type 1 diabetes and reported lifetime incremental cost‐effectiveness ratio (ICER) were included. Studies on critically ill or pregnant patients were excluded. Nineteen studies were identified. Most studies compared continuous subcutaneous insulin infusion and SMBG to a sensor‐augmented pump (SAP). The estimated ICER range was [$18,734–$99,941] and the quality‐adjusted life year (QALY) gain range was [0.76–2.99]. Use in patients with suboptimal management or greater hypoglycaemic risk revealed more homogenous results and lower ICERs. Limited studies assessed CGM in the context of multiple daily injections (MDI) (n = 4), MDI and SMBG versus SAP (n = 2) and three studies included hybrid closed‐loop systems. Most studies (n = 17) concluded that CGM is a cost‐effective tool. This systematic review suggests that CGM appears to be a cost‐effective tool for individuals with type 1 diabetes. Cost‐effectiveness is driven by reducing short‐ and long‐term complications. Use in patients with suboptimal management or at risk of severe hypoglycaemia is most cost‐effective. [ABSTRACT FROM AUTHOR]

Minimal sufficient balance (MSB) is a recently suggested method for adaptively controlling covariate imbalance in randomized controlled trials in a manner which reduces the impact on randomness of allocation over other approaches by only intervening when the imbalance is sufficiently significant. Despite its improvements, the approach is unable to consider the relative clinical importance or magnitude of imbalance in each covariate weight, and ignores any imbalance which is not statistically significant, even when these imbalances may collectively justify intervention. We propose the common scale MSB (CS‐MSB) method which addresses these limitations, and present simulation studies comparing our proposed method to MSB. We demonstrate that CS‐MSB requires less intervention than MSB to achieve the same level of covariate balance, and does not adversely impact either statistical power or Type‐I error. [ABSTRACT FROM AUTHOR]

Objective: Prior uncontrolled studies have reported seizure reductions following deep brain stimulation (DBS) in patients with Lennox–Gastaut syndrome (LGS), but evidence from randomized controlled studies is lacking. We aimed to formally assess the efficacy and safety of DBS to the centromedian thalamic nucleus (CM) for the treatment of LGS. Methods: We conducted a prospective, double‐blind, randomized study of continuous, cycling stimulation of CM‐DBS, in patients with LGS. Following pre‐ and post‐implantation periods, half received 3 months of stimulation (blinded phase), then all received 3 months of stimulation (unblinded phase). The primary outcome was the proportion of participants with ≥50% reduction in diary‐recorded seizures in stimulated versus control participants, measured at the end of the blinded phase. A secondary outcome was the proportion of participants with a ≥50% reduction in electrographic seizures on 24‐hour ambulatory electroencephalography (EEG) at the end of the blinded phase. Results: Between November 2017 and December 2019, 20 young adults with LGS (17–37 years;13 women) underwent bilateral CM‐DBS at a single center in Australia, with 19 randomized (treatment, n = 10 and control, n = 9). Fifty percent of the stimulation group achieved ≥50% seizure reduction, compared with 22% of controls (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 0.44–21.45, p = 0.25). For electrographic seizures, 59% of the stimulation group had ≥50% reduction at the end of the blinded phase, compared with none of the controls (OR= 23.25, 95% CI = 1.0–538.4, p = 0.05). Across all patients, median seizure reduction (baseline vs study exit) was 46.7% (interquartile range [IQR] = 28–67%) for diary‐recorded seizures and 53.8% (IQR = 27–73%) for electrographic seizures. Interpretation: CM‐DBS in patients with LGS reduced electrographic rather than diary‐recorded seizures, after 3 months of stimulation. Fifty percent of all participants had diary‐recorded seizures reduced by half at the study exit, providing supporting evidence of the treatment effect. ANN NEUROL 2022;91:253–267 [ABSTRACT FROM AUTHOR]

Aims: We reprocessed the Extending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) perfusion imaging with a different automated software with the aim of comparing mismatch eligibility and outcomes. Methods: EXTEND baseline perfusion imaging data were reprocessed using autoMIStar software to identify patients who were eligible based on the same target mismatch criteria as per the original trial. Results: From the 225 patients fulfilling RAPID‐based mismatch criteria randomized in the EXTEND study, 196 (87%) patients met the revised mismatch criteria. Most common reasons for not meeting revised criteria were core >70 ml (n = 9), and no perfusion lesion/lack of penumbral tissue (n = 20). The revised perfusion lesion volumes were significantly smaller compared to the original RAPID volumes (median 68 ml IQR 34–102 ml vs. 42 ml 16–92 ml, p = 0.036). Of the patients who met the revised mismatch criteria, 40% receiving alteplase had modified Rankin Scale (mRS) 0–1 at 3‐month compared to 28% with placebo (Adjusted Odds Ratio (OR) = 2.23, CI 1.08–4.58, p = 0.028). In contrast, in the original mismatch cohort, 35% receiving alteplase had mRS 0–1 at 3‐month compared to 30% with placebo (adjusted OR = 1.88, p = 0.056). Conclusions: These data reinforce the benefit of alteplase in the later time window, and suggest that differences in automated perfusion imaging software outputs may be clinically relevant. [ABSTRACT FROM AUTHOR]

Background: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. Aims: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. Methods: This single‐centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre‐determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. Results: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at‐risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. Conclusions: Dialysis patients are at risk of driving impairment based on self‐reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Individuals with diabetes frequently encounter sleep disturbances, which can detrimentally impact glycaemic management. We reviewed the relationship between sleep outcomes and glycaemic variability in adults with diabetes.We systematically searched Medline, EMBASE and Cochrane Library (2002‐March 2023) for studies evaluating sleep and glycaemic variability in adults with type 1 and type 2 diabetes. Among the 3049 records, 27 met the inclusion criteria (type 1 diabetes studies = 22). Due to methodological heterogeneity, a qualitative analysis was conducted.Most studies measuring sleep quality (5 out 7; 71%) reported a significant association with glycaemic variability in type 1 and type 2 diabetes. Sleep duration was not significantly associated with glycaemic variability in type 1 diabetes, whereas other sleep metrics yielded inconclusive results. Hybrid closed‐loop pump interventions (n = 12) demonstrated varying sleep outcomes with improved glycaemic variability. Similarly, sleep interventions (n = 3) consistently enhanced sleep but not glycaemic variability. Limitations included moderate to high risk of study bias, confounders, methodological heterogeneity and limited type 2 diabetes data.A potential association between sleep quality and glycaemic variability exists. However, associations with other sleep metrics remain elusive, with no discernible association between sleep duration and glycaemic variability in type 1 diabetes. Despite advancements in continuous glucose monitoring and ambulatory sleep monitoring, standardised sleep assessment methodologies are lacking in real‐world studies. Establishing standard protocols for sleep assessment and defining optimal sleep targets are crucial for meaningful comparisons between studies. Understanding the complex interplay between sleep and glycaemic variability holds promise in improving diabetes management and sleep health. [ABSTRACT FROM AUTHOR]

Background: Diabetes is 3‐4 times more prevalent in Indigenous Australians with blood glucose levels often above target range. Once weekly formulations of exenatide(exenatide‐LAR) have demonstrated significantly greater improvements in glycaemic management with no increased risk of hypoglycaemia and with reductions in bodyweight but have not been studied in Indigenous Australians. Aims: To assess the feasibility and metabolic effects of once weekly supervised injection of exenatide‐LAR in addition to standard care in Indigenous Australians with type 2 diabetes. Methods: Two communities in Central Australia with longstanding specialist clinical outreach services were allocated by random coin toss to receive once‐weekly exenatide‐LAR injection with weekly nurse review and adjustment of medication for 20 weeks (community with exenatide‐LAR) or to weekly nurse review in addition to standard care over 20 weeks (community without exenatide‐LAR). The primary outcome was the feasibility of an intensive diabetes management model of care with and without weekly supervised exenatide‐LAR. Secondary outcomes included change in HbA1c. Results: Thirteen participants from the community with exenatide‐LAR and nine participants from the community without exenatide‐LAR were analysed. Eighty‐five percent of individuals in the community with exenatide‐LAR and 67% in the community without exenatide‐LAR attended more than half of clinic visits. Median difference in the change in HbA1c from baseline to final visit, adjusted for baseline HbA1c, between the community with exenatide‐LAR and the community without exenatide‐LAR was −3.1%, 95% CI (−5.80%, −0.38%; P = 0.03). Conclusions: Weekly exenatide‐LAR combined with weekly nurse review demonstrated greater improvements in HbA1c, highlighting its potential for use in remote communities. [ABSTRACT FROM AUTHOR]

Background: Limited access to obstetrics and gynaecology (O&G) services in rural and remote Australia is believed to contribute to suboptimal birth outcomes. Aims: To describe the characteristics of pregnancy aeromedical transfers, in‐hospital outcomes, and patient access to O&G services, as compared to whole of Australia data. Materials and methods: We conducted a cohort study of women who required aeromedical retrieval for pregnancy‐related issues between the 1 January 2015 and 31 December 2017. Results: Hospital outcome data were collected on 2171 (65.2%) mothers and 2438 (100.0%) babies. The leading retrieval reason was threatened preterm labour and delivery (n = 883; 40.7%). Most patients were retrieved from rural and remote areas (n = 2224; 93.0%). Retrieved patients were significantly younger (28.0 vs 30.0 years, 95% CI 27.7–28.3), more likely to be overweight or obese (52.2% vs 45.1%, 95% CI 47.5–56.9) and to have smoked during their pregnancy (14.0% vs 9.9%, 95% CI 12.5–15.5) compared to Australian pregnant women overall. Over one‐third of transferred women gave birth by Caesarean section (n = 812; 37.4%); the median gestational age at birth was 33.0 (95% CI 32.7–33.3) weeks. Early gestation is associated with low birth weights (median = 2579.5 g; 95% CI 2536.1–2622.9), neonatal resuscitation (35.4%, 95% CI 33.5–37.3), and special care nursery admission (41.2%, 95% CI 39.3–43.2). There were 42 (1.7%, 95% CI 1.2–2.2) stillbirths, which was significantly higher than seen Australia‐wide (n = 6441; 0.7%). Conclusion: This study found that pregnant women retrieved by the Royal Flying Doctor Service were younger, with higher rates of obesity and smoking. [ABSTRACT FROM AUTHOR]

Background: Pre‐existing diabetes in pregnancy is associated with an increased risk of complications. Likewise, living in rural, regional and remote Victoria, Australia, is also associated with poorer health outcomes. There is a gap in the literature with regard to whether Victorian women with pre‐existing diabetes experience a greater risk of adverse pregnancy outcomes compared to their metropolitan counterparts. Aim: Our objective is to compare obstetric and perinatal outcomes for women with pre‐existing diabetes delivering in rural vs metropolitan hospitals in Victoria, Australia. Materials and Methods: Retrospective population‐based study using routinely collected state‐based data of singleton births to women with type 1 and type 2 diabetes who delivered in metropolitan (n = 3233) and rural hospitals (n = 693) in Victoria, Australia, between 2006–2015. Pearson's χ2 test, Fisher's exact test and MannWhitney U‐test were used to compare obstetric and perinatal outcomes between metropolitan and rural locations. Results: Delivery in a rural hospital was associated with higher rates of stillbirth (2.3% vs 1.1%, P = 0.027), macrosomia (25.9% vs 16.9%, P < 0.001), shoulder dystocia (8.4% vs 3.5%, P < 0.001) and admission to the neonatal intensive care unit/special care nursery (73.2% vs 59.3%, P < 0.001). Smoking (18.0% vs 8.9%, P < 0.001), overweight/obesity (P = 0.047) and socioeconomic disadvantage (P < 0.001) were more common in rural women. Conclusions: Women with pre‐existing diabetes who deliver in rural hospitals experience a greater risk of adverse perinatal outcomes and present with increased maternal risk factors. These results suggest a need to improve care for women with pre‐existing diabetes in rural Victoria. [ABSTRACT FROM AUTHOR]

Summary: Eligibility criteria for randomised control trials (RCT) in diffuse large B‐cell lymphoma (DLBCL) may be becoming increasingly strict. In this analysis, 42 first‐line phase III RCTs enrolling DLBCL patients since 1990 were identified from PubMed and clinicaltrials.gov. Changes in 31 individual eligibility criteria were assessed using three pre‐defined eras [(1) 1993–2005; (2) 2006–2013; and (3) 2014–2020]. The presence of 15/31 criteria increased significantly over time, and the total number of criteria per study also increased over time [median Era 1: 14·5, interquartile range (IQR) 12·6–16·4; Era 2: 21, 18·8–23·3; Era 3: 23, 21–25; P < 0·001]. When each trial's eligibility criteria were applied to 215 consecutive patients from an institutional database treated between 2010 and 2020, a median of 57% (IQR 47–70) of patients were hypothetically eligible for trial enrolment. The median percentage of patients eligible was 68% (56–91), 54% (37–81) and 47% (38–82) for Era 1, 2 and 3 respectively (P = 0·004). Phase III front‐line DLBCL trial criteria have become increasingly restrictive over the last three decades, resulting in a diminishing proportion of trial‐eligible patients, with less than 50% of our patients eligible for modern‐era studies. This potentially impacts generalisability of recent trial results and will likely limit recruitment to ongoing studies. [ABSTRACT FROM AUTHOR]

Background: BetterBrains is a prospective, blinded endpoint, 24‐month randomised controlled trial (RCT). It aims to test the effectiveness of an online, person‐centred, modifiable risk factor (RF) management program in delaying cognitive decline in middle‐aged adults (aged 40‐70) with a family history of dementia. This study aims to describe blinded baseline characteristics of the randomised sample and provide trial engagement statistics. Method: Participants enrolled in BetterBrains (betterbrains.org.au) complete all assessments on an online platform. RF assessment related to vascular health, sleep, mood, and social/cognitive engagement was conducted and participants with ≥1 RF were eligible. Participants complete assessments of cognition, general health, medical history, and lifestyle habits at baseline, 12, and 24‐months post‐randomisation. Primary outcome is absence of decline on at‐least one out of four cognitive tests at 24‐months. Participants randomised to the intervention arm receive a minimum of 6 person‐centred telehealth consultations over 12‐months with an allied health clinician trained in motivational interviewing. All participants receive monthly educational blogposts. Result: Since August 2021, 1518 participants have enrolled and 856 (56%) were randomised (Figure 1). Blinded baseline analyses reveal that randomised participants are mostly female (84%), white (93%), live in metropolitan areas (73%), and all report a first‐degree dementia family history. Mean age is 60 years (±6.7) and participants have 15.4 years of education (±3.9) on average. Mean number of reported RFs is 5 out of a possible 19. Readiness to change lifestyle behaviours to reduce dementia risk was high, with 71% of participants indicating implementation of at‐least some lifestyle changes prior to trial entry. Only 3% of randomised participants have withdrawn. Of participants who have reached 12‐months post‐randomisation (N = 349), 74% have completed follow‐up cognitive testing. Conclusion: Low attrition and high follow‐up rates suggest high acceptability and feasibility of the online BetterBrains methodology. The sample is likely at increased risk of dementia, due to high prevalence of first‐degree dementia family history, female gender, and co‐occurrence of multi‐domain modifiable dementia RFs. Presentation of findings will include a detailed breakdown of study methodology, baseline demographic/risk characteristics, and trial progress. [ABSTRACT FROM AUTHOR]

Background: Inflammatory mechanisms are increasingly recognized as part of the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Advances in analytical techniques using in vivo and postmortem samples have been applied to address questions of key mechanisms and relevance to clinical manifestations. Our primary objective was to review methods used to investigate inflammation in LBD (dementia with Lewy bodies and Parkinson's disease dementia), and how these are applied to conceptualise inflammation. Our secondary objective was to identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease, and compared to related neurodegenerative disease, in particular AD and PD. Method: A scoping review was performed by identifying relevant human studies that investigated inflammation in LBD. The major electronic databases MEDLINE, Embase, Web of Science, and PSYCHInfo were searched. Two authors performed abstract screening and full text review. Result: Of 1970 results screened, 65 studies were included. Twenty‐nine studies analysed postmortem brain tissue and 35 included living subjects. Largely cross‐sectional data were available, although 2 longitudinal clinical studies of prodromal Lewy body disease were noted. Analysis of biofluid (blood and cerebrospinal fluid) was the most common in vivo method used (n = 31) and 3 studies investigated LBD genetics. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, lymphocytes), and molecules linked to inflammation (e.g., cytokines). Results of included studies supported innate and adaptive immune system contribution to inflammation associated with Lewy body pathology and clinical features of the disease. Different signals in early and late‐stage disease, with possible late immune senescence including dystrophic microglia and altered adaptive immunity, were distinct from Alzheimer's disease. The strength of these associations is limited by the varying methodologies, small study sizes and cross‐sectional nature of data. Conclusion: Current investigation of inflammation in LBD utilises substrate collected from early to late‐stage disease. Strengths and limitations of the range of analytical techniques used must be considered when forming conclusions. Longitudinal data that informs associations with clinical and other biomarker outcomes is needed to improve understanding of inflammatory activity over the disease course of LBD. This could identify markers of disease activity and therapeutic targets. [ABSTRACT FROM AUTHOR]

While Alzheimer's disease (AD) is traditionally associated with deficits in episodic memory, early changes in other cognitive domains, such as attention, have been gaining interest. In line with clinical observations, some animal models of AD have been shown to develop attentional deficits, but this is not consistent across all models. The APPswe/PS1ΔE9 (APP/PS1) mouse is one of the most commonly used AD models and attention has not yet been scrutinised in this model. We set out to assess attention using the 5‐choice serial reaction time task (5CSRTT) early in the progression of cognitive symptoms in APP/PS1 mice, using clinically translatable touchscreen chambers. APP/PS1 mice showed no attentional changes across 5CSRTT training or any probes from 9 to 11 months of age. Interestingly, APP/PS1 mice showed increased impulsive and compulsive responding when task difficulty was high. This suggests that while the APP/PS1 mouse model may not be a good model of attentional changes in AD, it may be useful to study the early changes in impulsive and compulsive behaviour that have been identified in patient studies. As these changes have not previously been reported without attentional deficits in the clinic, the APP/PS1 mouse model may provide a unique opportunity to study these specific behavioural changes seen in AD, including their mechanistic underpinnings and therapeutic implications. [ABSTRACT FROM AUTHOR]

Problem: Antibody‐mediated autoimmune diseases, such as autoimmune thyroid diseases (ATD), systemic lupus erythematosus (SLE), and antiphospholipid syndrome (APS), often are associated with recurrent fetal loss. One of the ATD is Hashimoto's thyroiditis which recently showed association with complications of pregnancy with increased levels of circulating autoantibodies reactive with epitopes on thyroid tissue such as thyroid peroxidase (anti‐TPO). In retrospective study of sera analyses in patients with Hashimoto's thyroiditis, all patients had mainly elevated circulating anti‐TPO autoantibodies. Aim: We assessed the potential of human anti‐TPO highly positive IgG, derived from patients with Hashimoto's thyroiditis sera associated with complications of pregnancy, to cause directly complications of pregnancy in murine model. Method of study: Naïve ICR female mice, infused intravenously with 100 μg of anti‐TPO‐positive IgG, showed increased fetal loss and embryo small for date (P <.001) in comparison with mice passively transferred with commercial IgG or PBS. Moreover, we observed embryos small for date in the mice passively transferred with anti‐TPO‐positive IgG, exemplified by reduced weight of embryos and placentae (P =.001). Histopathological examination revealed delay in fetal development in 50% cases of anti‐TPO‐positive IgG‐treated mice. Importantly, pathological changes in the transition zone, state of glycogen cells, and significant structural changes in the labyrinth part of placenta were observed in all anti‐TPO‐positive IgG samples. Conclusion: The current study shows in the first time, a direct proof of concept, on the association of human TPO‐positive IgG from Hashimoto's thyroiditis patients on fetal loss induction in murine model. [ABSTRACT FROM AUTHOR]

Background: Little is known on the trends of aeromedical retrieval (AR) during social isolation. Aim: To compare the pre, lockdown, and post‐lockdown AR patient characteristics during a period of Coronavirus 2019 (COVID‐19) social isolation. Methods: An observational study with retrospective data collection, consisting of AR between 26 January and 23 June 2020. Results: There were 16 981 AR consisting of 1983 (11.7%) primary evacuations and 14 998 (88.3%) inter‐hospital transfers, with a population median age of 52 years (interquartile range 29.0–69.0), with 49.0% (n = 8283) of the cohort being male and 38.0% (n = 6399) being female. There were six confirmed and 230 suspected cases of COVID‐19, with the majority of cases (n = 134; 58.3%) in the social isolation period. As compared to pre‐restriction, the odds of retrieval for the restriction and post‐restriction period differed across time between the major diagnostic groups. This included, an increase in cardiovascular retrieval for both restriction and post‐restriction periods (odds ratio (OR) 1.12, 95% confidence interval (CI) 1.02–1.24 and OR 1.18 95%, CI 1.08–1.30 respectively), increases in neoplasm in the post restriction period (OR 1.31, 95% CI 1.04–1.64) and increases for congenital conditions in the restriction period (OR 2.56, 95% CI 1.39–4.71). Cardiovascular and congenital conditions had increased rates of priority 1 patients in the restriction and post restriction periods. There was a decrease in endocrine and metabolic disease retrievals in the restriction period (OR 0.72, 95% CI 0.53–0.98). There were lower odds during the post‐restriction period for retrievals of the respiratory system (OR 0.78, 95% CI 0.67–0.93), and disease of the skin (OR 0.78, 95% CI 0.6–1.0). Distribution between the 2019 and 2020 time periods differed (P < 0.05), with the lockdown period resulting in a significant reduction in activity. Conclusion: The lockdown period resulted in increased AR rates of circulatory and congenital conditions. [ABSTRACT FROM AUTHOR]

Objective: We sought to examine the diagnostic utility of existing predictors of any hemorrhagic transformation (HT) and compare them with new perfusion imaging permeability measures in ischemic stroke patients receiving alteplase only.Methods: A pixel-based analysis of pretreatment CT perfusion (CTP) was undertaken to define the optimal CTP permeability thresholds to predict the likelihood of HT. We then compared previously proposed predictors of HT using regression analyses and receiver operating characteristic curve analysis to produce an area under the curve (AUC). We compared AUCs using χ2 analysis.Results: From 5 centers, 1,407 patients were included in this study; of these, 282 had HT. The cohort was split into a derivation cohort (1,025, 70% patients) and a validation cohort (382 patients or 30%). The extraction fraction (E) permeability map at a threshold of 30% relative to contralateral had the highest AUC at predicting any HT (derivation AUC 0.85, 95% confidence interval [CI], 0.79-0.91; validation AUC 0.84, 95% CI 0.77-0.91). The AUC improved when permeability was assessed within the acute perfusion lesion for the E maps at a threshold of 30% (derivation AUC 0.91, 95% CI 0.86-0.95; validation AUC 0.89, 95% CI 0.86-0.95). Previously proposed associations with HT and parenchymal hematoma showed lower AUC values than the permeability measure.Interpretation: In this large multicenter study, we have validated a highly accurate measure of HT prediction. This measure might be useful in clinical practice to predict hemorrhagic transformation in ischemic stroke patients before receiving alteplase alone. ANN NEUROL 2020;88:466-476. [ABSTRACT FROM AUTHOR]

Background: Post‐operative complications following rectal resection pose significant health and cost implications for patients and health providers. The objective of this study is to review the associated cost of complications following rectal resection. This included reporting on the proportion and severity of these complications, associated length of stay and surgical technique used. Studies were sourced from Embase OVID, MEDLINE OVID (ALL) and Cochrane Library databases by utilizing a search strategy. Methods: This search contained studies from 1 January 2010 until 13 February 2019. Studies were included from the year 2010 to account for the implementation of enhanced recovery after surgery protocols. Studies that reported the financial cost associated with complications were included. Any indication for rectal resection was considered. Data was extracted into a formatted table and a narrative synthesis was performed. Results: We identified 13 eligible studies for inclusion. There was strong evidence to suggest that complications are associated with increased costs. There was considerable variation as to the costs attributable to complications ($1443 (P < 0.001) to $17 831 (P < 0.0012), n = 12). The presence of complications was associated with an increased length of stay (5.54 (P‐value not given) to 21.04 (P < 0.0001) days, n = 7). There was significant variation in the proportion of complications (6.41 to 64.71%, n = 8). Weak evidence existed around surgical technique used and the associated cost of complications. There was considerable heterogeneity among included studies. Conclusions: Complications following rectal resection increased health costs. Costs should be standardized and provide a clear methodology for their calculation. Complications should be standardized and include a grading of severity. [ABSTRACT FROM AUTHOR]

Background: Limited data exists concerning the health economics of liver resection, with even less information on the costs emerging from complications, despite this remaining an important target from a health economic perspective. Our objective was to describe the financial burden of complications following liver resection. Methods: We conducted a systematic search and included studies reporting resource use of in‐hospital complications during the index liver resection admission. All indications for liver resection were considered. All techniques were considered. Data was collected using a data extraction table and a narrative synthesis was performed. Results: We identified 12 eligible articles. There was considerable heterogeneity in study designs, patient populations and outcome definitions. We found weak evidence of increased costs associated with major liver resection compared to minor resections. We found robust evidence supporting the increasing economic burden arising from complications after liver resection. Acceptable evidence for increased cost due to the presence and grade of complication was found. Strong evidence concerning the association of length of stay with costs was demonstrated. Conclusions: The presence and grade of complications increase hospital cost across diverse settings. The costing methodology should be transparent and complication grading systems should be consistent in future studies. [ABSTRACT FROM AUTHOR]

Background and Purpose: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects.Experimental Approach: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task.Key Results: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest.Conclusions and Implications: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis. [ABSTRACT FROM AUTHOR]

Objective: We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias.Methods: We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling-related bias that may mimic anticipation.Results: Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02).Interpretation: Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3R451C). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3R451C mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. [ABSTRACT FROM AUTHOR]

Summary: Background: Decision support tools may facilitate shared decision‐making and improve quality of care. Aim: To assess the effectiveness of a decision support tool on improving quality of care in ulcerative colitis. Methods: A prospective quality of care intervention was conducted at two Australian hospitals comparing out‐patient–based ulcerative colitis care with, and without, a tablet‐based decision support tool. This included questions on disease activity management; psychological well‐being; and preventive care, with 13 process indicators relevant to each domain. Participants included adult out‐patients with mild‐to‐moderate ulcerative colitis and their clinicians who were divided into two cohorts. The first cohort were followed up immediately after their clinical review to check whether their clinician had discussed the 13 process indicators during the consultation. The second cohort of patients used the decision support tool immediately prior to their consultation which then generated a suggested management plan for the patient and clinician to discuss during the consultation. Management between the 2 cohorts was compared to assess the effectiveness of the decision support tool in improving the primary outcome, defined as the proportion of quality process indicators used for ulcerative colitis care, with and without the decision support tool. Results: Thirteen physicians and 100 patients participated. Fifty patients were managed without the decision support tool using standard care (median age 40; 44% male), and 50 patients used the decision support tool (median age 40; 46% male) over a 20‐week period. Increase in the median use of process indicators overall was observed following use of the decision support tool (27% vs 100%; P < 0.001). Improvements were seen in psychological well‐being management (30% vs 100%; P < 0.001), preventive care (16% vs 100%; P < 0.001) and process indicators related to disease activity management (50% vs 100%; P < 0.001). The decision support tool was found to be usable and acceptable. Shared decision‐making was greater in the post‐intervention group (mean decision conflict score of 18.0 vs 33.5; P = 0.002). Conclusions: The decision support tool substantially improved the quality of the delivery of care. Decision support tools have the potential to minimise errors of omission via a standardised approach to care. [ABSTRACT FROM AUTHOR]

Background: Recent guidelines suggest screening high‐risk women in early pregnancy for gestational diabetes (GDM); however, there is little evidence to support this. Aims: To compare pregnancy outcomes associated with diabetes for women with risk factors for GDM according to gestation of diagnosis. Early GDM was defined as a positive test before 20 weeks gestation, late GDM as a positive test at 20 or more weeks and no GDM when both tests were negative. Materials and methods: Retrospective analysis in an Australian tertiary hospital of women who underwent a glucose tolerance test in pregnancy prior to 20 weeks gestation, and a repeat test after 20 weeks gestation if the initial test was negative. Results were adjusted for maternal demographics. Results: Women with early GDM (n = 170) were no more likely to experience the obstetric composite outcome than women with late GDM (n = 171) or no GDM (n = 547) (early odds ratio (OR) 1.16, 95%CI 0.79–1.71; late OR 0.78, 95%CI 0.53–1.12). Infants of women with early GDM, but not late GDM, were more likely (early OR 1.8, 95%CI 1.15–2.92; late OR 1.4, 95%CI 0.90–2.23) to have the neonatal composite outcome than infants of women without GDM, predominantly due to an increase in neonatal hypoglycaemia. Conclusions: This result may be due to careful management of GDM, or because, after adjustment for maternal demographics, the early diagnosis of GDM does not substantially increase rates of adverse outcomes compared to GDM diagnosed in later pregnancy or no GDM in women with risk factors for GDM. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) are often associated with vascular risk factors and/or cerebral amyloid angiopathy and are frequently identified in people with dementia. This study aimed to estimate the pooled prevalence of CMB across the three most common late‐onset dementia diagnoses, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Method: A systematic search with pre‐defined search terms was performed on Medline, EMBASE and PubMed, from inception to 19th October 2022. Identified articles were manually screed for titles and abstracts by independent reviewers. Relevant MRI studies that reported raw prevalence data of CMB in AD, DLB or PDD were included. Studies which investigated Parkinson's disease without dementia or people with mild cognitive impairment were excluded. Prevalence data were manually extracted, and study quality was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. Data were pooled using random‐effect models. The predefined primary outcome was prevalence of CMB in AD, DLB and PDD. Secondary outcomes were associations between CMB and vascular risk factors as well as amyloid‐β burden. Result: A total of 65 studies met the inclusion criteria for data extraction. CMB, predominantly lobar, were present in 32% of AD (n = 5409; 95% CI 29‐35%), 36% of DLB (n = 348; 95% 26‐45%) and 31% of PDD participants (n = 236; 95% CI 23‐40%). The prevalence estimates of CMB in AD and DLB increased with higher field strength and the use of susceptibility‐weighted imaging. CMB in AD were associated with a history of hypertension (odds ratio [OR] 1.74, 95% CI 1.33‐2.28) and amyloid‐β burden (standardised mean difference [SMD] 0.41; 95% CI 0.25‐0.57). CMB in DLB were associated with hypertension (OR 1.95; 95% CI 1.00‐3.83), but not amyloid‐β burden (SMD 0.05; 95% CI ‐0.32‐0.42). Conclusion: The prevalence of CMB was similar across AD, DLB and PDD (31‐36%). The underlying pathophysiology of CMB in DLB might differ from that of AD. More studies evaluating CMB in DLB and PDD are needed. [ABSTRACT FROM AUTHOR]

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Background. The ineffectiveness of most complex stroke recovery trials may be explained by inadequate intervention design. The primary aim of this review was to explore the rationales given for interventions and dose in stroke rehabilitation randomised controlled trials (RCTs). Methods. We searched the Cochrane Stroke Group library for RCTs that met the following criteria: (1) training based intervention; (2) >50% participants who were stroke survivors; (3) full peer-reviewed text; (4) English language. We extracted data on 16 quality items covering intervention dose (n= 3), trial design (n= 10), and risk of bias (n= 3) and 18 items related to trial method. Logistic regression analyses were performed to determine whether (1) reporting of trial quality items changed over time; (2) reporting of quality items was associated with the likelihood of a positive trial, adjusted for sample size and number of outcomes. Results. 27 Cochrane reviews were included, containing 9,044 participants from 194 trials. Publication dates were 1979 to 2013, sample size was median 32 (IQR 20,58), and primary outcome was reported in 49 trials (25%). The median total quality score was 4 (IQR 3,6) and improved significantly each year (OR 1.12, 95% CI 1.07, 1.16, p<0.001). Total quality score was not associated with likelihood of a positive trial, but trials containing a biological rationale for the intervention were more likely to find a difference in patient outcome (OR 2.18, 95% CI 1.14, 4.19, p=0.02). Conclusion. To develop breakthrough treatments we need to build the rationale for research interventions and testing of intervention dosage. This will be achieved through a collective research agenda to understand the mechanistic principles that drive recovery and identification of clearer targets for clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Endovascular clot retrieval (ECR) following intravenous thrombolysis is superior to intravenous thrombolysis alone for acute stroke with large vessel occlusion. However, trial selection criteria may exclude potentially salvageable patients. We investigated the impact of published selection criteria on the different proportions of patients excluded and clinical outcome.Methods: We included patients with anterior circulation stroke treated with ECR from a single centre. Selection criteria from five trials (REVASCAT, EXTEND IA, MR CLEAN, SWIFT PRIME, ESCAPE) and American Stroke Association (ASA) guidelines were applied. We calculated the proportion of patient's ineligible for ECR according to different selection criteria. Clinical benefit and harm were quantified as the number of patients benefiting per 1 patient harmed (NB1H) for each of the 6 applied selection criteria.Results: One hundred and seventy-eight patients were included. Mean age was 74 (SD 14) years, 60.1% were male, median baseline NIHSS was 17 (IQR 13-21). Patients were hypothetically excluded from ECR: REVASCAT 35.4%, EXTENDA IA 86%, SWIFT PRIME 86%, MR CLEAN 2.3%, ESCAPE 93.3% and ASA 29.2%. The NB1H for included and excluded patients respectively in decreasing order of magnitude: EXTEND IA >100 vs 3, ESCAPE >100 vs 3.4, SWIFT PRIME 10 vs 3.3, REVASCAT 4.4 vs 2.9, MR CLEAN 3.7 vs >100, and ASA 3.7 vs 3.9.Conclusion: We found that criteria from MR CLEAN, ASA and REVASCAT excluded the lowest proportion of patients with comparable NB1H. We believe that these criteria would be reasonable to be utilised for ECR selection. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the attitudes of patients with different cancers towards research biopsies outside a clinical trial. Methods: Patients with metastatic cancer completed a questionnaire that assessed patients' willingness to consider research biopsies. Research biopsies were divided into two groups: biopsies performed as stand-alone procedures (research purposes only biopsy, RPOB) or performed during a clinically indicated biopsy (additional pass biopsy, APB). Factors analyzed included biopsy timing, biopsy site, sociodemographic information and information about prior trial participation. Univariate and multivariable analyses were conducted using random-effects logistic regression. Results: One hundred and sixty-five patients with cancer (40 melanoma, 37 colorectal, 32 breast, 30 lung, 26 prostate) completed the questionnaire. Patients with melanoma demonstrated the greatest willingness to consider a research biopsy compared to patients with other cancer types (P < 0.05). Patients' ethnicity, time since previous biopsies, time since metastatic diagnosis, and previous trial enrolment were all statistically significant for willingness to consider a research biopsy on univariate analysis. When adjusting for statistically significant variables on univariate analysis, the odds of patients considering APBs were 14.6 times greater than RPOBs (P < 0.0001). Patients were also more willing to consider having blood or skin taken for research purposes (P < 0.0001) compared to liver and bone biopsies. Conclusions: Patients with cancer show a greater willingness to consider APBs compared to RPOBs, and biopsies performed at less invasive body sites. There are differences in the attitudes of patients with different cancers towards research biopsies. Further research addressing motivations and barriers to research biopsies should be considered to increase the availability of this important resource. [ABSTRACT FROM AUTHOR]

Abstract: Background: Routine chest X‐ray (CXR) is recommended for neutropenic fever (NF) management however its role is relatively understudied in haematology patients. Aim: To investigate the utility of CXR in the diagnosis and management of patients with haematological conditions complicated by NF. Methods: Retrospective, single‐centre analysis of haematology patients admitted with NF between January 2011 and December 2015. Baseline demographics, treatment details and outcomes were collected from electronic patient records. CXR underwent independent radiology review. Primary endpoints were a proportion of NF episodes in which CXR detected a probable chest infection in the absence of respiratory symptoms/signs and/or resulted in a change in antibiotic management. Results: Four hundred and thirty‐five episodes were identified; CXR was performed in 75% of patients (65% within 2 days of NF). In 4 of 164 (2.4%) asymptomatic patients, CXR was consistent with infection, in contrast to 19 of 119 (16%) patients with clinical signs of respiratory infection. Only 3 of 283 (1.1%) CXR resulted in a change to antibiotics. CXR consistent with infection was not associated with increased mortality or increased admission length, although there was an association with intensive care unit admission (odds ratios: 7.61, 95% confidence interval: 2.04–28.31). Conclusion: In haematology patients with NF, CXR rarely detected chest infection or changed management in patients with no respiratory symptoms or signs. CXR in our institution is no longer part of routine assessment of NF in the absence of these features. [ABSTRACT FROM AUTHOR]

Summary: Objective: Endovascular therapy has recently become standard therapy for select patients with acute ischemic stroke. Infarcted brain tissue may undergo hemorrhagic transformation (HT) after endovascular therapy. We investigated the association between HT and occurrence of poststroke seizures in patients treated with endovascular therapy. Methods: Consecutive patients treated with endovascular therapy for acute anterior circulation ischemic stroke were included. HT was assessed with computed tomography/magnetic resonance imaging (CT/MRI) at 24 h after stroke onset. Patients were followed for up to 2 years for seizure occurrence. Results: A total of 205 (57.1% male) patients were analyzed. Median age was 69 years (interquartile range [IQR] 57‐78). Among patients with HT, 17.9% (10/56) developed poststroke seizures compared with 4.0% (6/149) among those without HT (hazard ratio [HR] 5.52; 95% confidence interval [CI] 2.00‐15.22; P = .001). The association remained significant after adjustment for cortical involvement, baseline National Institutes of Health Stroke Scale score, age and use of intravenous tissue plasminogen activator and clot retrieval (HR 4.85; 95% CI 1.60‐14.76; P = .005). In patients who developed seizures within the follow‐up period, median time to first seizure was 111 days (IQR 28‐369) in patients with HT and 36 days (IQR 0.5‐183) in patients without HT. Significance: A patient who develops HT following endovascular therapy for acute ischemic stroke had a nearly 5 times higher rate of developing poststroke seizures within 2 years. HT may be used as an imaging biomarker for poststroke seizures. [ABSTRACT FROM AUTHOR]

Background Preoperative anaemia is associated with increased morbidity and mortality in surgical patients. Recent national patient blood management guideline recommended screening surgical patients for anaemia, particularly iron deficiency anaemia, without reference to the prevalence of anaemia or iron deficiency anaemia in this patient population. Aims To establish the prevalence and cause of preoperative anaemia in elective major surgery patients. Methods Patients attending the anaesthetic pre-admission clinics from 1 July 2013 to 30 June 2014 prior to their major elective surgery in our institution were screened for anaemia and iron deficiency by measuring full blood count, iron studies and C-reactive protein. Patients who were anaemic were either further assessed in the haematology clinic or had their medical records reviewed to ascertain the cause of the anaemia. Results Of 1494 patients, 208 (13.9%) were anaemic, with a male predominance (70.7%); 57 (27.4%) of them had iron deficiency anaemia. Other common causes of anaemia include underlying malignancy (18.3%), end-stage renal failure (11.5%) and other chronic diseases (7.2%). In 53 patients (25.5%), the cause was unknown. Anaemia was most commonly found in patients scheduled for gastrointestinal surgery. Conclusion Preoperative anaemia affects 13.9% of patients undergoing elective major surgery. The most common causes are iron deficiency and chronic diseases. The cause was unexplained in 25.5% of patients with anaemia. The prevalence of anaemia in different surgical specialties may have implications on the approach to screening, particularly in resource-limited areas. [ABSTRACT FROM AUTHOR]

It is unknown if high prolactin levels during pregnancy contribute to the development of gestational diabetes. We hypothesized that higher prolactin levels are associated with reduced glucose tolerance, as determined by higher 2-h glucose level from an oral glucose tolerance test in pregnancy. The 75-g oral glucose tolerance test was carried out at 28 weeks of gestation in 69 participants. A multiple regression analysis was used to determine the relationship between serum prolactin and 2-h glucose levels. Multivariable regression analysis showed an independent and significant relationship between third trimester prolactin and 2-h glucose levels post oral glucose tolerance test. Higher prolactin levels were associated with higher glucose levels independent of age, body mass index, gravidity and parity. Higher prolactin levels associated with reduced glucose tolerance in the third trimester of pregnancy suggests the possible independent role of prolactin in the pathogenesis of gestational diabetes. [ABSTRACT FROM AUTHOR]

The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model. Human KCTD12 co-expression altered the kinetics of GABABR-mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration-response curves showed that KCTD12 coexpression did not alter effects of the agonists GABA or baclofen on GABABR. KCTD12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP7930, and its effects on GABABR activation and desensitization. The function of KCTD12 in vivo was examined, using the KCTD12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD12 accelerated the kinetics of GABABR in vitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel in vivo evidence that the interaction between KCTD12 and GABABR is of physiological significance, and may be a mechanism to more selectively modulate GABABR. [ABSTRACT FROM AUTHOR]

Background and purpose: Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined. Methods: This was a prospective, multicentre, cluster-randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients hospitalized for stroke/transient ischaemic attack and aged 18 years were recruited from four hospitals. General practices treating recruited patients were randomized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care. The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months. Results: From January 2010 to November 2013, 156 general practices (280 patients) were randomly assigned to usual care (control) and 159 (283 patients) to the intervention. The median age was 70.1 years; 65% were male. Overall, >80% of participants were prescribed recommended secondary prevention therapies at baseline. The primary efficacy analysis comprised 533 participants, with 30 either dying or lost to follow-up. In adjusted analyses, no significant between-group difference was found in the cardiovascular risk score at 12 months (0.04, 95% confidence interval 1.7, 1.8). Conclusions: The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practices. [ABSTRACT FROM AUTHOR]

Objectives: Hospital data used to assess regional variability in disease management and outcomes, including mortality, lack information on disease severity. We describe variance between hospitals in 30-day risk-adjusted mortality rates (RAMRs) for stroke, comparing models that include or exclude stroke severity as a covariate.Design: Cohort design linking Australian Stroke Clinical Registry data with national death registrations. Multivariable models using recommended statistical methods for calculating 30-day RAMRs for hospitals, adjusted for demographic factors, ability to walk on admission, stroke type, and stroke recurrence.Setting: Australian hospitals providing at least 200 episodes of acute stroke care, 2009-2014.Main Outcome Measures: Hospital RAMRs estimated by different models. Changes in hospital rank order and funnel plots were used to explore variation in hospital-specific 30-day RAMRs; that is, RAMRs more than three standard deviations from the mean.Results: In the 28 hospitals reporting at least 200 episodes of care, there were 16 218 episodes (15 951 patients; median age, 77 years; women, 46%; ischaemic strokes, 79%). RAMRs from models not including stroke severity as a variable ranged between 8% and 20%; RAMRs from models with the best fit, which included ability to walk and stroke recurrence as variables, ranged between 9% and 21%. The rank order of hospitals changed according to the covariates included in the models, particularly for those hospitals with the highest RAMRs. Funnel plots identified significant deviation from the mean overall RAMR for two hospitals, including one with borderline excess mortality.Conclusions: Hospital stroke mortality rates and hospital performance ranking may vary widely according to the covariates included in the statistical analysis. [ABSTRACT FROM AUTHOR]

Aims We aim to explore whether people with epilepsy have increased white matter hyperintensities ( WMHs). Methods Eligible patients were categorized into newly diagnosed epilepsy ( NE) and chronic epilepsy ( CE); the latter were subdivided to those treated with enzyme-inducing antiepileptic drugs ( EIAEDs) with or without non-enzyme-inducing antiepileptic drugs ( NEIAEDs) and those with NEIAEDs only. WMHs were measured using age-related white matter changes ( ARWMC) scale and compared between patients and healthy control group. Higher scores indicate greater WMH changes. The strengths of associations were estimated as incidence rate ratios ( IRRs) with 95% confidence interval ( CI). Results A total of 217 patients were included in the analysis, of whom 67 had NE, 45 had CE treated with NEIAEDs, and 105 had CE treated with EIAEDs. Age was positively associated with ARWMC score ( IRR per year, 1.03; 95% CI, 1.03-1.04, P < 0.001). Compared with the healthy control group (n = 23), all patient groups had higher ARWMC score ( P < 0.05). The difference was greatest in patients receiving EIAEDs ( IRR, 2.13; 95% CI, 1.22-3.70, P = 0.007). Conclusions WMHs tended to be observed in people with epilepsy, especially in those treated with EIAEDs. People with epilepsy with white matter changes should be evaluated for stroke risk, particularly if they are receiving EIAEDs. [ABSTRACT FROM AUTHOR]

Aims: We aimed to evaluate early recanalization postintravenous (i.v.) tissue plasminogen activator (t-PA) by digital subtraction angiography (DSA) in acute ischemic stroke (AIS) with large vessel occlusion (LVO). Methods: We performed baseline CT angiography to identify LVO in AIS. Recanalization pre- and post-intra-arterial therapy (IAT) was categorized to none, partial, and global recanalization (GR). Modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome. Results: Among 1610 patients with AIS, 286 received IV t-PA. Of these, 55 patients with LVO were included. The median time from IV t-PA to DSA was 120 min (interquartile range, 79-152). Recanalization post-IV t-PA was observed in seven patients (12.7%). By occlusion sites, the recanalization rates were as follows: extracranial internal carotid artery 2 of 14 (14.3%); intracranial internal carotid artery 3 of 24 (12.5%); M1 of middle cerebral artery 3 of 39 (7.7%); M2 of middle cerebral artery 1 of 40 (2.5%); vertebral artery 0 of 4; and basilar artery 0 of 7. GR post-IAT was associated with favorable outcomes (odds ratio: 8.6; 95% confidence interval, 1.5-48.0; P = 0.014). Conclusion: Early recanalization assessed by DSA post-IV t-PA is rarely observed in acute ischemic stroke patients with LVO. [ABSTRACT FROM AUTHOR]